P2Y receptors are G-protein-coupled receptors (GPCRs) that are selectively activated by naturally occurring extracellular nucleotides, including, for example, adenine and pyrimidine nucleotides. There are two clusters of P2Y receptors: the Gq-coupled P2Y1-like receptors, including P2Y1, 2, 4, 6, 11 subtypes; and the Gi-coupled P2Y12-like receptors, including P2Y12, 13, 14 subtypes. Of the four P2Y receptors, i.e., P2Y2, 4, 6, 14 subtypes, which can be activated by pyrimidine nucleotides, the P2Y2 and P2Y4 subtypes are activated by uridine triphosphate (UTP), P2Y6 receptor is activated by uridine diphosphate (UDP), and P2Y14 is activated by UDP or UDP-glucose.
The P2Y6 receptor has been implicated in a number of disorders, including, for example, neurodegeneration, osteoporosis, ischemic effect in skeletal muscle, and diabetes. It has been reported that agonists of P2Y6 receptor counteract apoptosis induced by tumor necrosis factor α in astrocytoma cells and induce protection in a model of ischemic hindleg skeletal muscle. P2Y6 receptor was also reported to play a role in phagocytosis in microglial cells when activated by its endogenous agonist UDP. See, e.g., Malmsjo et al. BMC Pharmacol. 2003, 3, 4; Balasubramanian et al. Biochem. Pharmacol. 2010, 79, 1317-1332; Kim et al. Cell. Mol. Neurobiol. 2003, 23, 401-418; Mamedova et al. Pharmacol. Res. 2008, 58, 232-239; Korcok et al. J. Biol. Chem. 2005, 58, 232-239; and Koizumi et al. Nature, 2007, 446, 1091-1095. These reports suggest that ligands of the P2Y6 receptor are of interest in the search for new treatments for P2Y6 receptor-related conditions.
Therefore, there is a need for new ligands, such as agonists, of the P2Y6 receptor that are useful in therapeutic preparations for the treatment of disorders responsive to the receptor, including neurodegeneration, traumatic brain injury and pain.